Medical Research Council Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, National Hospital forNeurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom

Communicated by Charles Weissmann, The Scripps Research Institute, Jupiter, FL, January 10, 2008 (received for review October 10, 2007)

Kuru provides our principal experience of an epidemic human priondisease and primarily affected the Fore linguistic group of theEastern Highlands of Papua New Guinea. Kuru was transmitted bythe practice of consuming dead relatives as a mark of respect andmourning (transumption). To date, detailed information of theprion strain type propagated in kuru has been lacking. Here, wedirectly compare the transmission properties of kuru prions withsporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD)prions in Prnp-null transgenic mice expressing human prion proteinand in wild-type mice. Molecular and neuropathological data fromthese transmissions show that kuru prions are distinct from variantCJD and have transmission properties equivalent to those ofclassical (sporadic) CJD prions. These findings are consistent withthe hypothesis that kuru originated from chance consumption ofan individual with sporadic CJD.

snip...

Discussion

In the present study, we have compared the transmission propertiesof kuru prions with sporadic, iatrogenic, and variant CJDprions in transgenic mice expressing human PrP valine 129 andin wild-type mice. These data establish that kuru prions havetransmission properties equivalent to those of classical CJDprions and are distinct from vCJD prions. In agreement with thisfinding, the molecular strain types of PrPSc seen in kuru braincorrespond to those seen in classical CJD rather than the distinctPrPSc types seen in vCJD or inherited prion disease. Thesecollective data establish that kuru and classical CJD prions haveclosely similar prion strain properties and are consistent with thehypothesis that kuru originated from chance consumption of anindividual with sporadic CJD (43).Human prion diseases with distinct etiologies are associatedwith a range of clinical presentations that are now seen asclinicopathological syndromes rather than individual diseaseentities (4, 55, 56). The central clinical feature of kuru isprogressive cerebellar ataxia, and, in sharp contrast to sporadicCJD, dementia is a late and less prominent feature. A prodromeand three clinical stages consisting of an ambulatory stage, asedentary stage, and a tertiary stage have been described in ref.20. In this regard, the natural history of kuru is more reminiscentof vCJD in which early symptoms of distal sensory disturbance,joint pains, and psychiatric and behavioral changes are commonbefore forthright dementia (4, 23, 25, 28). Despite these similaritiesin early clinical presentation, the molecular and neuropathologicalfeatures of kuru are distinct from vCJD. In contrastto the occurrence of abundant florid PrP plaques that are theneuropathologicalchanges seen in kuru lie within the spectrum ofthose seen in sporadic CJD. Unicentric PrP plaques, however,are unusually prominent and widespread (58, 59). This patternof neuropathology most closely resembles a relatively raresubtype of sporadic CJD associated with long clinical durationand PRNP codon 129 heterozygosity in which kuru-type PrPplaques are also observed (10, 11, 46).Although PrP plaques are not a prominent feature of the mostcommon subtypes of sporadic CJD, where diffuse synaptic PrPdeposition predominates (10, 11, 46, 60), kuru-type plaques area notable feature of iatrogenic CJD resulting from peripheralinoculation, most conspicuously after cadaveric pituitaryderivedhormone exposure (61). This form of iatrogenic CJDalso typically presents with a progressive cerebellar syndromereminiscent of kuru, whereas cases of iatrogenic CJD arisingfrom intracerebral or ocular inoculation usually manifest clinicallyas sporadic CJD, with a rapidly progressive dementia(62–65). These observations suggest that cerebellar onset andsubsequent neuropathological changes may be determined inpart by a peripheral route of exposure. The similarity of prionstrain type in kuru and sporadic CJD demonstrated here nowclearly suggests that peripheral routes of infection (predominantlydietary), rather than prion strain type, may be an importantdeterminant of the clinicopathological phenotype of kuru.In this regard, the etiology of sporadic CJD remains unclear,although its remarkably uniform worldwide incidence and apparentlyrandom distribution suggest involvement of a stochasticprocess such as somatic PRNP mutation (2, 48, 66, 67). It is thuspossible that part of the phenotypic and neuropathologicalheterogeneity seen in sporadic CJD could be related to peripheralversus central initiation of prion replication.Aside from route of exposure, additional factors may alsoinfluence the neuropathology and clinical features of kuru. Anumber of genetic modifiers of prion disease have been mappedin mice (16, 17). Although the genes responsible for mouseincubation time quantitative trait loci have not yet been identified,orthologous human genes are likely to be globally polymorphicwith significant differences within and between Europeand the Fore. Furthermore, age is an important determinant ofyouth may be associated with an atypical sporadic CJD neuropathology(70). The marked difference in mean age of kuru andsporadic CJD patients might thus account for some of theneuropathological differences that distinguish kuru from themajority of sporadic CJD cases.Our finding that kuru prions and vCJD prions have verydifferent transmission properties supports previous molecular(9, 45–47, 49, 50), neuropathological (25, 57, 58), and transmission(14, 15, 26, 27) data indicating that vCJD is a highly distincthuman prion strain. The pathogenesis of vCJD differs significantlyfrom that of other forms of human prion disease. PrPSc isreadily detectable in lymphoreticular tissues in vCJD and not inclassical CJD or inherited prion disease (29, 32, 47, 71–76).Because kuru, iatrogenic CJD, and vCJD are caused by aperipheral route of exposure to infectious prions, it is possiblethat extensive lymphoreticular pathogenesis may result from thiscommon route of exposure. However, the fact that tonsillar prioninfection has not been detected in iatrogenic CJD associatedwith use of human cadaveric derived pituitary hormone (72, 75)or kuru (unpublished data) suggests that the distinct peripheralpathogenesis of vCJD is determined by prion strain type alonerather than route of infection.Although distinct from the vCJD prion strain, kuru is criticallyimportant as our only precedent of an orally acquired humanprion disease epidemic. There remain striking parallels betweenthe two outbreaks in terms of their clinical features, restrictedtemporal and geographic distribution, and the long and variableincubation times observed. Profound disease susceptibility isconferred by PRNP codon 129 in both diseases (4, 5, 15, 22).Because mouse models of prion disease demonstrate the importanceof a small number of non-Prnp genetic factors in controlof incubation time, it will be important to understand how theorthologous human genes modify susceptibility or incubation toboth kuru and vCJD. ...snip...end...tss

well, i guess this just tells ya not to eat your neighbor, (besides the fact my mom died from the hvCJD, my neighbors mom also died from sCJD, both cases confirmed). OR just maybe the atypical h-BASE, which is very similar to some sporadic CJD pathologically, via consumption of h-base atypical BSE USA CATTLE, is the cause of some of these sporadic CJD cases in the USA ??? or, what about the l-base and the TME ??? it's getting dicey now folks, OR maybe a little mix of the NOR-98 atypical scrapie (nowdocumented in 5 different states). hmmm, i am thinking Mission, Texas. ALSO, what about all those downers i.e. 95%+ deadstock downer cow feeder i.e. TME mink outbreaks. OR, what a minute now, i am not through, what about the CWD and very likely potential there for multiple strains. it's all coming together folks, the USA is a smorgasbord for all kinds of human and animal TSE, via many different routes and sources.thus, the BSE MRR policy was born, the legal trading of all strains of TSE, globally, all for a buck $$$

PROBLEMS SOLVED, ''MISSION ACCOMPLISHED'' ! GOD BLESS AMERICA !

WE already knew that sporadic CJD would transmit to primate by non-forced oral consumption ;

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. ...

3.57 The experiment which might have determined whether BSE and scrapie werecaused by the same agent (ie, the feeding of natural scrapie to cattle) wasnever undertaken in the UK. It was, however, performed in the USA in 1979,when it was shown that cattle inoculated with the scrapie agent endemic inthe flock of Suffolk sheep at the United States Department of Agriculture inMission, Texas, developed a TSE quite unlike BSE. 32 The findings of theinitial transmission, though not of the clinical or neurohistologicalexamination, were communicated in October 1988 to Dr Watson, Director of theCVL, following a visit by Dr Wrathall, one of the project leaders in thePathology Department of the CVL, to the United States Department ofAgriculture. 33 The results were not published at this point, since theattempted transmission to mice from the experimental cow brain had beeninconclusive. The results of the clinical and histological differencesbetween scrapie-affected sheep and cattle were published in 1995. Similarstudies in which cattle were inoculated intracerebrally with scrapie inoculaderived from a number of scrapie-affected sheep of different breeds and fromdifferent States, were carried out at the US National Animal Disease Centre.34 The results, published in 1994, showed that this source of scrapie agent,though pathogenic for cattle, did not produce the same clinical signs ofbrain lesions characteristic of BSE.

http://www.bseinquiry.gov.uk/

The findings of the initial transmission, though not of the clinical orneurohistological examination, were communicated in October 1988 to DrWatson, Director of the CVL, following a visit by Dr Wrathall, one of theproject leaders in the Pathology Department of the CVL, to the United StatesDepartment of Agriculture. 33

http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf

12/10/76AGRICULTURAL RESEARCH COUNCILREPORT OF THE ADVISORY COMMITTE ON SCRAPIEOffice NoteCHAIRMAN: PROFESSOR PETER WILDY

snip...

A The Present Position with respect to ScrapieA] The Problem

Scrapie is a natural disease of sheep and goats. It is a slowand inexorably progressive degenerative disorder of the nervous systemand it ia fatal. It is enzootic in the United Kingdom but not in allcountries.

The field problem has been reviewed by a MAFF working group(ARC 35/77). It is difficult to assess the incidence in Britain fora variety of reasons but the disease causes serious financial loss;it is estimated that it cost Swaledale breeders alone $l.7 M duringthe five years 1971-1975. A further inestimable loss arises from theclosure of certain export markets, in particular those of the UnitedStates, to British sheep.

It is clear that scrapie in sheep is important commercially andfor that reason alone effective measures to control it should bedevised as quickly as possible.

Recently the question has again been brought up as to whetherscrapie is transmissible to man. This has followed reports that thedisease has been transmitted to primates. One particularly luridspeculation (Gajdusek 1977) conjectures that the agents of scrapie,kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy ofmink are varieties of a single "virus". The U.S. Department ofAgriculture concluded that it could "no longer justify or permitscrapie-blood line and scrapie-exposed sheep and goats to be processedfor human or animal food at slaughter or rendering plants" (ARC 84/77)"The problem is emphasised by the finding that some strains of scrapieproduce lesions identical to the once which characterise the humandementias"

Whether true or not. the hypothesis that these agents might betransmissible to man raises two considerations. First, the safetyof laboratory personnel requires prompt attention. Second, actionsuch as the "scorched meat" policy of USDA makes the solution of theacrapie problem urgent if the sheep industry is not to suffergrievously.

snip...

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf

SCRAPIE DOCUMENTED IN CLINICAL SUSPECT GOAT, WITH TWO MORE DOCUMENTED IN SAME BIRTH HERD OF CLINICAL CASE

INFECTED AND SOURCE FLOCKS AS of August 31, 2007, there were 33 scrapieinfected and source flocks with open statuses (Figure 3). Five new sourceflocks and one new infected flock were reported n August (Figure 4) with atotal of 64 reported for FY 2007(Figure 5).

snip...

IN FY 2007 TWO FIELD CASES, ONE VALIDATION CASE, AND TWO RSSS CASES WERECONSISTENT WITH NOR-98 SCRAPIE. ...